Tumor targeting and microenvironment-responsive multifunctional fusion protein for pro-apoptotic peptide delivery. (28th June 2019)

• Record Type: Journal Article
• Authors: Yin, Jun; Liu, Dingkang; Bao, Lichen; Wang, Qun; Chen, Ye; Hou, Shan; Yue, Yali; Yao, Wenbing; Gao, Xiangdong
• Is Part Of: Cancer letters. Volume 452(2019)
• Page Start: 38
• Page End: 50
• Publication Date: 2019-06-28
• Subjects: Polypeptide -- Matrix metalloproteinase 2 -- Targeted therapy -- Anticancer peptide; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2019.03.016
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: The great therapeutic potential of peptides has not yet been achieved, mainly due to their remarkably short in vivo half-life. Although conjugation to macromolecules has been an effective way of improving protein in vivo half-life, the steric hindrance of macromolecules usually reduces the in vivo efficacy of peptides. Here we report a complex delivery system made from PsTag polypeptide, polyglutamic acid chain, matrix metalloproteinase 2 (MMP2)-degradable domain and cationic cell penetrating peptide for anticancer peptide delivery. Clear evidence was shown in vitro and in vivo to demonstrate that this multifunctional protein fusing a pro-apoptotic KLAKLAKKLAKLAK (KLA), named PAK, can increase circulation time in blood, enhance accumulation at tumor sites, eliminate the PsTag domain and the polyanionic sequence when triggered by tumor overexpressing MMP2, and then expose the cell penetrating peptide to realize the potent cellular uptake of KLA. Treatment of tumor-bearing mice with PAK could markedly induce tumor cells apoptosis and inhibit tumor growth, with no significant adverse effects. These results suggest our fusion protein can be a potential delivery system for peptide delivery in cancer treatments. Highlights: A multifunctional protein-tagged strategy for tumor-targeted peptide delivery. PsTag could block the activity of KLA and achieve the fusion expression in E. coli. The microenvironment-responsive protein (PAK) achieved enhanced tumor accumulation. PAK showed minimal hemolytic activity, low immunogenicity, stability in serum. PAK showed high in vivo anti-tumor activity with no significant side effects.